rs5936

chr2-127423296-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000312.4(PROC):c.423G>T(p.Ser141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.682 in 1,549,898 control chromosomes in the GnomAD database, including 362,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36480 hom., cov: 36)
  • Exomes 𝑓: 0.68 (325588 hom.)
• Consequence: PROC NM_000312.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.81

Genes affected

PROC (HGNC:9451): (protein C, inactivator of coagulation factors Va and VIIIa) This gene encodes a vitamin K-dependent plasma glycoprotein. The encoded protein is cleaved to its activated form by the thrombin-thrombomodulin complex. This activated form contains a serine protease domain and functions in degradation of the activated forms of coagulation factors V and VIII. Mutations in this gene have been associated with thrombophilia due to protein C deficiency, neonatal purpura fulminans, and recurrent venous thrombosis.[provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-127423296-G-T is Benign according to our data. Variant chr2-127423296-G-T is described in ClinVar as [Benign]. Clinvar id is 255809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-127423296-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.81 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROC	NM_000312.4	c.423G>T	p.Ser141=	synonymous_variant	6/9	ENST00000234071.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROC	ENST00000234071.8	c.423G>T	p.Ser141=	synonymous_variant	6/9	1	NM_000312.4	P1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105153 AN: 152022 Hom.: 36471 Cov.: 36

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.682

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.693

GnomAD3 exomes AF: 0.678 AC: 100470 AN: 148168 Hom.: 34891 AF XY: 0.661 AC XY: 52156 AN XY: 78878

Gnomad AFR exome AF: 0.721

Gnomad AMR exome AF: 0.833

Gnomad ASJ exome AF: 0.711

Gnomad EAS exome AF: 0.562

Gnomad SAS exome AF: 0.522

Gnomad FIN exome AF: 0.677

Gnomad NFE exome AF: 0.686

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.680 AC: 951060 AN: 1397762 Hom.: 325588 Cov.: 85 AF XY: 0.675 AC XY: 465408 AN XY: 689444

Gnomad4 AFR exome AF: 0.711

Gnomad4 AMR exome AF: 0.820

Gnomad4 ASJ exome AF: 0.709

Gnomad4 EAS exome AF: 0.642

Gnomad4 SAS exome AF: 0.522

Gnomad4 FIN exome AF: 0.685

Gnomad4 NFE exome AF: 0.687

Gnomad4 OTH exome AF: 0.674

GnomAD4 genome AF: 0.691 AC: 105200 AN: 152136 Hom.: 36480 Cov.: 36 AF XY: 0.688 AC XY: 51165 AN XY: 74370

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.692

Gnomad4 EAS AF: 0.572

Gnomad4 SAS AF: 0.520

Gnomad4 FIN AF: 0.685

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.686

Alfa AF: 0.696 Hom.: 19198

Bravo AF: 0.704

Asia WGS AF: 0.548 AC: 1905 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Thrombophilia due to protein C deficiency, autosomal dominant Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Thrombophilia due to protein C deficiency, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	3.3
Dann	Benign	0.77
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5936; hg19: chr2-128180872; COSMIC: COSV52164601; COSMIC: COSV52164601;